Steroid hormones are necessary for good health in humans. [Witzmann, R., Steroids: Keys to Life, Van Nostrand Reinhold Co., New York, N.Y., 1977; Hammes, S. R., Proc. Nat'l. Acad. Sci. 2003, 1009 21680-21700.] For example, these compounds are useful in the treatment and/or prevention of cancer, dermatological disorders, bone disorders, parathyroid disorders, immunological disorders, wound healing and osteoporosis. Over the years, diverse oxa steroids have been prepared to probe how the replacement of a —CH2 group by an O-atom affects biological activity. Significant and valuable biological benefits have been recorded for some oxa steroids including: (1) 6-oxa steroids as GABAA receptor modulators [Nicoletti, S. R. et al., Steroids 2000, 65, 349-356]; (2) 7-oxa steroids as potent and selective progesterone receptor antagonists [Kang, F. A. et al.; Bioorg. Med. Chem. Lett. 2007, 17, 907-910]; (3) 11-oxa steroids as progestational agents [Engel, C. R. et al.; Steroids 1986, 47, 381-399; Cachoux, F.; Tetrahedron Lett. 2000, 41, 1767-1769]; and (4) 15-oxa steroids as estrogenic agents [Rosen, P. et al.; J. Med. Chem. 1980, 23, 329-330].
Some oxa analogs of the vitamin D seco-steroids have also been reported [Calverley, M. J. et al.; Analogues, U.S. Pat. Nos. 5,378,695 and 5,401,732 (1995)]. The most noteworthy oxa analog of the natural hormone 1α,25-dihydroxyvitamin D3 (calcitriol, A) is the Chugai Pharmaceutical Company's maxacalcitol B [Kubodera, N., Current Bioactive Compounds 2006, 2, 301-315]. This 22-oxa-25-OH analog is currently a clinically used drug for the treatment of secondary hyperparathyroidism and is a drug candidate for the topical treatment of psoriasis, an immune-mediated, chronic skin disease. Other 23-oxa-25-hydroxy analogs of the natural hormone A have been studied, but none surpasses or even matches Chugai's drug 22-oxa-25-hydroxy B in terms of favorable separation of antiproliferative and/or prodifferentiation activity from unfavorable calcemic activity. [Steinmeyer, A., et al.; Curr. Pharm. Des. 2000, 6, 767-789] For example, in a broad study of structure-activity relationships (SAR) in 23-oxa-25-hydroxy analogs of A, the Schering Corporation found that the potential therapeutic window between desirably high antiproliferative or prodifferentiation activity and desirably low calcemic activity was small for 23-oxa calcitriol, 20-ene-23-oxa calcitriol, and 22-ene-25-oxa calcitriol [Steinmeyer, A., et al.; Curr. Pharm. Des. 2000, 6, 767-789], compared to a big therapeutic window for the Chugai drug 22-oxa-25-hydroxy B. [Allewaert, K. et al.; Steroids 1994, 59, 686-690].
Thus, what is needed in the art are other analogs of the vitamin D seco-steroids that selectively exhibit desirable pharmacological activities but not exhibit hypercalcemic and other undesirable activities.